{
  "abstract": "Mitochondrial DNA (mtDNA) base editors (mtBEs) are promising tools for studying and correcting pathogenic mtDNA mutations. However, the application of mtBEs is often hindered by substantial mtDNA-wide off-target editing that accumulates with prolonged mtBE expression resulting from plasmid DNA or viral delivery. To overcome this limitation, we developed mtBE-VLPs, a virus-like-particle (VLP) platform for transiently delivering mtBEs in vitro and in vivo with minimal off-target effects. While canonical protein-packaging VLPs yielded undetectable mtDNA base editing, engineered mRNA-packaging VLPs enabled efficient but transient mtBE cargo delivery. By iteratively engineering mRNA-packaging VLP compositions, we improved mtBE-VLP-mediated base editing efficiencies from less than 1% to greater than 50% across multiple target mtDNA loci in bulk populations of treated cultured cells. To further improve the packaging and delivery of certain mtBEs, we developed a strategy to selectively reduce mtBE cargo expression in VLP producer cells but not transduced cells, which increased VLP-mediated base editing efficiencies for certain mtBEs by 7.1-fold. Compared to plasmid DNA delivery in vitro, mtBE-VLPs exhibited equivalent on-target editing but 23- to 41-fold lower mtDNA-wide off-target editing, highlighting the improved editing specificity offered by transient mtBE delivery. mtBE-VLPs efficiently installed a pathogenic mtDNA mutation in mouse embryonic fibroblasts (88% efficiency) and corrected a pathogenic mtDNA mutation in a human patient-derived cell line (41% efficiency). Additionally, a single subretinal injection of mtBE-VLPs yielded 6-20% (average 12%) mtDNA base editing in the mouse retinal pigment epithelium with minimal mtDNA-wide off-target editing. These findings establish mRNA-packaging mtBE-VLPs as promising vehicles for efficient and precise mitochondrial base editing via transient mtBE delivery.",
  "abstract_shown": true,
  "affiliations": [
    "Whitehead Institute for Biomedical Research"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "name": "H. Jang"
    },
    {
      "name": "C. Rodrigues Menezes"
    },
    {
      "name": "K. Palczewski"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Raguram"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/98pw7bj7404jd.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.04.756548",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756548v1.full",
  "id": "98pw7bj7404jd",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756548v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioengineering"
    ],
    [
      "openalex",
      "1312|CRISPR and Genetic Engineering"
    ]
  ],
  "openalex": "W7220404198",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756548v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/98pw7bj7404jd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:02Z",
      "native_id": "10.64898/2026.10.04.756548",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756548v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Engineered mRNA-packaging virus-like particles enable efficient and precise mitochondrial base editing in vitro and in vivo",
  "title_text": "Engineered mRNA-packaging virus-like particles enable efficient and precise mitochondrial base editing in vitro and in vivo",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:02Z",
  "url": "https://research.draconitic.com/paper/98pw7bj7404jd",
  "venue": "bioRxiv",
  "versions": []
}